Structural Spectroscopy and Dynamics of Inter- and Intramolecular H-Bonding Interactions of Topotecan, a Potent Anticancer Drug, in Organic Solvents and in Aqueous Solution

Abstract

We report on the role of H-bonding interactions on the UV-visible absorption and emission (steady-state and time-resolved) spectroscopy of topotecan (TPT) in solution. In aprotic solvents, a very fast (less than 10 ps) excited-state intramolecular proton-transfer reaction occurs in the absorbing enol (E) form to give a zwitterion (Z) form, emitting with a large Stokes shift. In protic solvents like methanol, the time constant of Z* formation is longer (32 ps) due to the participation of solvent molecules in the proton-transfer reaction. In aqueous solution at near-neutral pH (6.24), a ground-state equilibrium is established between E, cation (C), and Z forms. Direct excitation of E leads to Z* through two channels: a very fast one (less than 10 ps) involving an intramolecular proton-tranfer and a slower one (680 ps) with the C* intermediate formation and reaction. A fast (42 ps) deprotonation of E* to give the excited anion (A*) also competes with the photoformation of Z* at the S(1) state. At pH =12.15, the A structures are the principal emitting species (τ(A) ~ 0.41 ns), showing the largest Stokes shift. In aqueous solutions, we cannot exclude the existence of an equilibrium between the lactone and carboxylate forms of TPT, whose spectroscopic (absorption and emission spectra) and dynamical behaviors should not be very different. Time-resolved emission anisotropy measurements in solvents of different viscosities suggest that the rotational relaxation time (φ) of TPT is mainly governed by the viscosity of the medium, increasing from 104 ps (in tetrahydrofuran, THF) to 156 ps (in water) and 338 ps (in dimethyl sulfoxide, DMSO). These results give spectroscopic and dynamical information on the structures, stability, and dynamics (picosecond to nanosecond time scale) of TPT in solution. They provide insights on the role of the intermolecular H-bonding surrounding medium on the ground- and excited-state structure and reaction of TPT. The finding should contribute to a better understanding of the relationship between the structures of the drug and its surroundings.

Dynamics of different steps of the photopyrolytic cycle of an eminent anticancer drug topotecan inside biocompatible lyotropic liquid crystalline systems

“…2). [36][37][38] Here it is pertinent to mention that although the cationic (C) form of the drug is selectively excited at 380 nm ( Fig. S2 in ESI †), the uorescence appears from Z* form (532 nm) of TPT.…”

“…This has been attributed to the excited state intermolecular proton transfer (ESPT) process by which water-assisted deprotonation of the 10-hydroxyl group takes place, and leads to the conversion of C* to Z* form of the drug. [36][37][38] Thus, it is believe that the excited state conversion of C* to Z* is the dominating photophysics of TPT in aqueous solutions of neutral pH. [36][37][38] However, in bulk monolinolein (GML) the emission spectrum exhibits a single emission peak at $425 nm (Fig.…”

“…[36][37][38] Thus, it is believe that the excited state conversion of C* to Z* is the dominating photophysics of TPT in aqueous solutions of neutral pH. [36][37][38] However, in bulk monolinolein (GML) the emission spectrum exhibits a single emission peak at $425 nm (Fig. 2) corresponding to the cationic (C*) form of the drug.…”

“…Interestingly, combination of 6-hydroxy quinoline (A and B rings) and 9-dimethylaminomethylene group gives rise to different protolytic forms of TPT in their ground as well as in excited state. [36][37][38] In physiological conditions TPT exhibits equilibrium between enol (E), cationic (C) and zwitterionic (Z) forms in ground state (Scheme 2).…”

“…36,38,39 The formation of Z* form in excited state is believed to be an outcome of the 'excited state proton transfer (ESPT)' from -OH group of C* form to the nearby water molecule. 36,38,39 As ESPT process of TPT is sensitive to polarity, 36,38,39 the ESPT process can be modulated inside conned media, where polarity is signicantly different compared to bulk water. Hence, ESPT dynamics have been probed inside conned media, such as, calixarenes, 40 cucurbituril, 37 reverse micelle, 39 etc.…”